Nrf2 overexpression increases the resistance of acute myeloid leukemia to cytarabine by inhibiting replication factor C4

Abstract

Drug resistance is a key factor in the treatment failure of acute myeloid leukemia (AML). Nuclear factor E2-related factor 2 (Nrf2) plays a crucial role in tumor chemotherapy resistance. However, the potential mechanism of Nrf2 regulating DNA mismatch repair (MMR) pathway to mediate gene-instability drug resistance in AML is still unclear. Here, it was found that Nrf2 expression was closely related to the disease progression of AML as well as highly expressed in AML patients with poor prognostic gene mutations. Meanwhile, it was also found that the expression of Nrf2 was significantly negatively correlated with DNA MMR gene replication factor C4 (RFC4) in AML. CHIP analysis combined with luciferase reporter gene results further showed that Nrf2 may inhibit the expression of RFC4 by its interaction with the RFC4 promoter. In vitro and vivo experiments showed that the overexpression of Nrf2 decreased the killing effect of chemotherapy drug cytarabine (Ara-C) on leukemia cells and inhibited the expression of RFC4. Mechanistically, The result that Nrf2-RFC4 axis mediated AML genetic instability drug resistance might be received by activating the JNK/NF-κB signaling pathway. Taken together, these findings may provide a new idea for improving AML drug resistance.

TAZ upregulates MIR‐224 to inhibit oxidative stress response in multiple myeloma

“…Several studies suggest that NRF2 mediates tumor growth, metabolism, and chemotherapy resistance in solid tumors 38,39,57,58 . In agreement with these reports, previous studies in leukemia, lymphomas, and MM have shown that upregulation of the NRF2 antioxidant pathway increases tumor resistance to cytotoxic chemotherapy 59–62 . Herein we show that miR‐224 or TAZ may downregulate NRF2 expression in myeloma cells (Figure 4B–D) to enhance their sensitivity to antimyeloma chemotherapies.…”

“… 38 , 39 , 57 , 58 In agreement with these reports, previous studies in leukemia, lymphomas, and MM have shown that upregulation of the NRF2 antioxidant pathway increases tumor resistance to cytotoxic chemotherapy. 59 , 60 , 61 , 62 Herein we show that miR‐224 or TAZ may downregulate NRF2 expression in myeloma cells (Figure 4B–D ) to enhance their sensitivity to antimyeloma chemotherapies. Importantly, NRF2 expression in patient samples shows an inverse relationship with TAZ in a publicly available database (Figure 4F ).…”

Oncogenic Potential of Replication Factor C Subunit 4: Correlations with Tumor Progression and Assessment of Potential Inhibitors

“…In vivo, in vitro, and in silico studies have reported Cytarabine potential effects on RFC4, which are mainly associated with cell cycle and mitosis [ 23 , 24 ]. Nelarabine, in combination with other chemotherapies, was able to reduce RFC4 gene expression [ 25 ].…”

Drug-induced oxidative stress in cancer treatments: Angel or devil?

“…However, OS can also damage normal tissues that rapidly proliferate, such as gastrointestinal tract, bone marrow and hair follicles, leading to cardiac, hepatic, pulmonary, renal and gastrointestinal toxicities [ 119 , 120 ] ( Table 1 ). Additionally, other adverse events reduce the efficacy of chemotherapy and promote cancer metastasis and recurrence, such as cancer cell adaptation to OS, cell cycle alterations by OS, or CSC escape from oxidative damage [ [121] , [122] , [123] ]. Therefore, pro-oxidant therapy has two major drawbacks in cancer treatment: side effects and drug resistance.…”